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Rachel Upjohn Clinical Scholar Awards

The goal of this award, established in 1998, is to train a new generation of clinical investigators focusing their research on depression, bipolar disorder, and related illnesses. The Rachel Upjohn Clinical Scholars program offers support to those young researchers who have chosen to devote a major part of their research efforts toward the study of depression. The fund honors Rachel Mary Upjohn Meader. Mrs. Meader and her husband Edwin were among the most ardent supporters of the mission and work of the Depression Center during their lifetimes

Daniel Healy
Will riluzole and aniracetam treatments induce time-dependent changes in glutamate receptor expression that will result in sustained changes in NMDA receptor expression, the candidate substrate for hippocampal cell loss in MDD

1999

Jonathan Metzl
Assessing the Clinical Impact of Direct to the Consumer Advertisements for Antidepressants

Atypical antipsychotics have detrimental side effects, including weight gain, hypertension, diabetes, and high cholesterol, often referred to as “metabolic syndrome.” Within the bipolar population treated with atypical antipsychotics, the incidence of metabolic syndrome is twice that of the general population, which has contributed significant reductions in life expectancy of up to 25 years for these patients. It is unknown how the expression of our genes as controlled through a process called DNA methylation relates to metabolic syndrome. This study will help clinicians use this information to create better approaches to treating bipolar patients with atypical antipsychotics while reducing side effects.

GREAT will assess the feasibility and acceptability of a group exercise intervention for adolescents with depression and bipolar disorder. Dr. Dopp’s two previous studies on the impact of exercise on depression in adolescents have included only individual sessions in the intervention. Secondary outcomes for GREAT include 1) changes in activity levels and depression severity and 2) assessment of exercise’s impact on serum biomarkers and a cortisol biomarker (hair sample). Participants will carry pedometers every day during the 12-week intervention to provide immediate feedback regarding their aerobic exercise, document levels of physical activity, and assess compliance with protocol expectations. Insulin and glucose levels will contribute to our understanding of the relationships among aerobic exercise, certain metabolic processes, and insulin resistance. Brain-derived neurotrophic factor is a biomarker which changes with aerobic exercise and has important roles in learning, memory, and mood regulation.

David Tai Hsu, M.D.Peer victimization, brain opioids, and the risk for major depressive disorder

Studies have found that as high as 45-70% of American adolescents are victims of peer victimization at school (e.g., bullying, hurtful teasing). Peer victimization can negatively impact mental health, causing low self-esteem and depression. Although peer victimization has been well studied by social psychologists, there is a significant gapin the understanding of the biological link between peer victimization and the risk for depression. We have previously shown that social rejection activates the endogenous opioid system, which may function to facilitate recovery from social distress. The goalof this study is to examine the response of the endogenous opioid system to experimental social rejection in young adults (ages 18-25) with a history of adolescent peer victimization. This represents the first study to examine a neurochemical response to social rejection in young adults with a history of peer victimization, uncovering a potential biomarker for those at risk for depression.

Nestor Lopez-Duran, Ph.D. Early neuroendocrine markers of depression in adolescents: Vulnerability or Prodrome?

This study aims to study how different aspects of the body’s endocrine stress system are linked to the onset of depression in high-risk adolescents. It will examine whether anomalies within these systems reflect a vulnerability (risk) of the individual that increases the risk for depression or instead reflect that the depression process has already begun. The study will involve examining whether changes in endocrine processes predict the onset of depression in teens at familial risk for depression by following 60 families for at least 12 months. The results of this study may help researchers and clinicians improve their diagnostic practices, select youth who may best benefit from prevention programs, and develop new treatments.

Biomarkers are needed to improve treatment of major depression and bipolar disorder. Mood disorders and antidepressant therapies have been linked with the γ-aminobutyric acid system, or GABA -- the brain's major inhibitory neurotransmitter. GABA deficits have been consistently demonstrated in depressive disorders. Furthermore, human and preclinical studies have shown that GABA deficits are ameliorated by antidepressant treatments such as medication and electroconvulsive therapy (ECT). Genetic variation may predispose some individuals to low levels of GABA in the brain, thereby influencing the individual's type of depression or response to treatment. This project will search for gene variants that predispose to low GABA, altered brain function, and differences in response to electroconvulsive therapy and long-term outcomes. Findings could lead to clinically useful biomarkers based on the brain's GABA system, which could ultimately improve diagnosis and longitudinal management of depressive illnesses.

Depressive illness in pregnancy is common and has been identified as a risk factor for poor maternal and child outcomes including preterm delivery, low child birth weight, and increased long-term risk for mental health problems in the children themselves. Thus, early detection and effective treatment for maternal depression in pregnancy is crucial, as is increased understanding of the pathways by which a mother’s depression in pregnancy may negatively impact her unborn child. Current research has begun to identify several biological substrates (biomarkers) that may constitute risk or protection, but we still do not understand the exact mechanisms underlying these processes. This study will explore how several currently validated biomarkers for depression (sleep, inflammatory markers, stress and bonding hormone) shape the course of depressive illness during pregnancy and potentially influence the mother’s treatment response to a non-pharmacological intervention (yoga) during pregnancy. The findings from this research have the potential to inform both research and clinical work to prevent transmission of risk to the unborn child.

The identification of blood biomarkers in major depression has the potential to improve our ability to diagnose and following the course of the disorder, to uncover novel disease pathways and, ultimately, to produce better treatments for patients suffering from depression. Markers of cardiovascular function represent a class of potential depression biomarkers. Depressed patients are at markedly increased risk of cardiovascular disease and altered levels of a series of factors that are markers of cardiovascular health. However, no clear evidence shows whether changes in these factors precede the onset of depressive symptoms or are consequences of the disorder.

During the period of medical internship, we can reliably predict when a cohort of individuals will experience a sharp increase in the rates of depression. A four-year study across 14 institutions examining psychological, demographic and genetic predictors of depression during the stress of internship has found that rates of depression increase dramatically, from 4% prior to internship to 26% during internship year.

In this project, the research team plans to assess a set of blood biomarkers in a sample of medical interns before exposure to internship stress, when rates of depression are low, and again after 12 months of internship. The team will prospectively assess whether markers of cellular senescence, such as DNA hypomethylation and reduced telomere length, as well as markers of endothelial and inflammatory function change with chronic stress, and whether changes correlate with the increase in depressive symptoms. Because this study assesses individuals before and after the onset of a stressor, it has the potential to produce a major impact on our understanding of the relationship between cardiovascular health and depression.

The internship model allows for the assessment of potential biomarkers when participants are under low stress with few depressive symptoms and for following the participants as they develop greater depressive symptoms. Ten institutions have committed to taking part in this study, which will make it possible to collect the large samples necessary needed to achieve the power to identify depression biomarkers with small to moderate effects. The Rachel Upjohn funding will help the study team include participants at additional sites and generate high-quality pilot data and feasibility data on collaborating across sites for a future NIMH grant. This project holds the promise to substantially improve the way that we diagnose and treat major depression.

Youth with untreated depression are at higher risk for a variety of negative outcomes, including school drop-out, peer and family conflicts, and suicide. Stigma around mental illness can often be one of the most significant obstacles to the provision of effective treatments to those who need them. This project intends to promote school-based interventions to educate elementary and middle school youth about depression, targeting barriers to service utilization among at-risk youth. The study involves evaluating and disseminating results of a completed randomized controlled trial of a depression education and stigma reduction intervention for African-American middle school youth (supported in part by a Ouida award [link to page]) and also collecting pilot data and refining research procedures to evaluate a newly developed mental health education curriculum for elementary schools.

Current research confirms that very young children, as early as preschool age, may manifest clinical depression, and longitudinal follow-up studies have underscored that young children identified with depression experience high levels of chronicity and/or recurrence in subsequent years. Thus from a clinical and public health perspective, the very early detection of depression, and effective targeted interventions, are needed to counteract long-lasting adverse developmental outcomes. In adolescents and adults, several biological markers (including sleep architecture/circadian rhythms, HPA stress axis functioning, and pro-inflammatory cytokines) have been identified as robust predictors of concurrent or subsequent depression. Measuring these biomarkers in infancy and exploring their association with genetic risk status may potentially identify risk for later depressive illness, thus permitting targeted interventions prior to the manifestation of full blown illness in the preschool years.

This study aims to identify whether previously established biological risk markers for depressive illness in adolescence and adulthood are also valid risk markers in early childhood. This line of inquiry is both innovative and highly clinically relevant, as elucidating early markers may alter early risk trajectories, leading to early detection, prevention, and more effective treatments for at-risk infants based on phenotype and genotype, with corresponding improved childhood outcomes.
Capitalizing on an existing longitudinal data set (from a study supported by a 2007 Rachel Upjohn award, “Maternal Anxiety during the Childbearing Years [link to anchor on this page, if possible]) that follows infants of mothers with psychopathology (depression and PTSD), the study involves examining infants at risk for biological dysregulation in infancy and following them longitudinally into the preschool years. The study aims to identify associations between infant sleep architecture, HPA stress reactivity, levels of pro-inflammatory cytokines among infants with and without genetic risk, and maternal depression status, as well as to explore associations of infant biomarkers with subsequent onset of depressive symptoms in early childhood.

Kimberly Nylen, Ph.D.Rates and Predictors of Patient Retention, Adherence, And Treatment Response In A Clinic-Based Sample Of Perinatal Women: Establishing Infrastructure For Specialty Clinic Research (2010)

Perinatal depression represents a significant public health concern and affects nearly 20% of childbearing women. It has been linked to adverse outcomes that include infant preterm delivery and low birth weight, as well as maternal disturbances in functioning across a number of domains, such as relationships with partners and children. Although efficacious treatments for perinatal depression have been identified, perinatal depression remains underdetected and undertreated. Of the small percentage of women who do receive treatment for perinatal mood disturbances, the vast majority do not receive adequate treatment and do not report significant improvement in depression or functioning. Thus, there is a substantial need to investigate predictors of patient retention, adherence, and treatment outcome, with the ultimate goal of improving clinical care for depressed perinatal women.

This study aims to examine rates and predictors of treatment retention and adherence in a clinic-based sample of perinatal women, and, as a secondary aim, identify predictors of treatment outcome in a subset of women who naturalistically completed a follow-up measure eight weeks following treatment initiation. Among many goals, this study aims to provide preliminary information on predictors of retention, adherence, and response to specialty perinatal depression care, and to establish the infrastructure and feasibility of conducting hypothesis-driven clinical research to be competitive for an NIH R21 application focusing on this patient population. It is anticipated that this project will ultimately lead to projects designed to develop improved diagnostic and treatment approaches for perinatal depression and anxiety, as well as depression more generally.

Alan Prossin, M.D.The Impact of IL-1RA on the Sensory and Affective Dimensions of Pain in Treatment Resistant Depression (2010)

Major Depressive Disorder (MDD) affects close to 15% of Americans, is the number one cause of work-related absences, and is highly co-morbid with medical illness such as chronic pain states. In fact, patients with co-morbid MDD and chronic pain states have been found to have significantly reduced quality of life and symptom severity than in those patients having either condition occurring alone. There appears to be a reciprocal relation between depression and certain pain states, and, consequently, some of the treatments that assist with the amelioration of depressive symptoms have also proven to be of some benefit in the treatment of pain states and vice versa. Directing novel treatment strategies requires a better understanding of the mechanisms that produce both depressive states and chronic pain states.

Cytokines are defined as ‘a varied group of small secreted proteins that mediate cellular interactions in immune and inflammatory responses, cell proliferation and differentiation, and various other processes’. There is increasing recognition that peripheral (i.e. blood-borne) inflammatory cytokines play a role in the stress response, emotion regulation, and stress-related pathological states, including MDD and chronic pain. This study intends to examine the relationship between plasma levels of IL-1 family cytokines (i.e. IL-1ß, IL-1RA) and sensory and affective components of pain, and internal affective state in healthy controls and patients with MDD. These data will be employed as preliminary information for the development of a federal NIH grant application aimed at linking peripheral cytokines with alterations in endogenous opioid system function in treatment refractory MDD and persistent pain states.

Katherine Rosenblum, Ph.D.The Circle of Security Pilot: Establishing the Efficacy of a Preventive Intervention for Young Children at Risk for Mental Health Problems (2010, 2009, 2008)

The Circle of Security intervention is a relationship-focused parenting group that promotes sensitive caregiving and facilitates child-attachment security in a supportive environment. Intervention participants are mothers with a history of trauma or who have an insecure-type relationship with their child. Dr. Rosenblum has conducted this project in collaboration with Maria Muzik. The Rachel Upjohn Clinical Scholar awards have supported implementation and evaluation of two Circle of Security groups.

Preliminary analyses reveal that a mother’s participation in the COS intervention directly and positively impacts attachment security – all mother-child pairs identified as demonstrating insecure attachment before the group became securely attached after group participation. Such robust preliminary results reinforce the efficacy of the Circle of Security intervention group with particularly high-risk women and their children. In addition, the research team found that mothers reported lower behavior problems in their children on standard behavioral rating scales (CBCL, Achenbach 1991) after the intervention. Using brain imaging, the study will examine maternal parenting brain circuitry in upcoming COS groups, aiming to expand the understanding of brain function within a parenting and attachment-based context. Moreover, it will be the first study to examine how treatment gains related to a parenting intervention may be evident in maternal neurocircuitry.

This data is being compiled as preliminary data for an NIMH/NICHD grant submission, and the research group is also writing several internal (CTSA-MICHR) and external NIH grants to continue and expand this line of research. The Circle of Security intervention will not only continue to provide treatment and care for high-risk women, but will ultimately contribute to the understanding of how intervention programs can be tailored to specifically suit the needs of mothers with a history of trauma and posttraumatic stress. The present study is consistent with the overarching research goal of gaining a more comprehensive understanding of how a mother’s trauma experience and psychopathology influences her caregiving capabilities and her child’s outcomes, and, perhaps most importantly, how intervention can occur early in these trajectories in order to ameliorate risky outcomes for both mother and child across development. This work has also received support from the Todd Ouida Scholar Awards Fund.

Increased reports of depressive states following cytokine treatments for several disorders has demonstrated a direct relationship between the immune system and depression. However, the mechanisms by which the immune system is linked to depressive states is far from clear. Dr. Blandino’s project is examining immune genes associated with depression in post-mortem brains of individuals that were diagnosed with schizophrenia, with and without comorbid expression of depression. The amygdala brain region of the brain is of particular interest, due to this region’s association with mood regulation and the high number of immune genes observed to change in this region in the context of depression.

Part of Dr. Blandino’s post-doc appointment is collaborative with the Pritzker Consortium through Dr. Huda Akil’s laboratory. The Consortium is comprised of investigators at Stanford, UC Davis, UC Irvine, Cornell, The Hudson-Alpha Institute and here at the University of Michigan. This collaborative effort draws upon a brain bank at UC Irvine for which a new cohort of samples was obtained. This new cohort includes 24 post-mortem brain samples from schizophrenic individuals with 13 indicating comorbid depression and 11 without comorbid depression; a dramatic increase in the number of subjects that previously proposed and available on hand. Furthermore, there will be 24 control samples available rather than the 8 originally indicated in the grant proposal. Together this new cohort will allow for more subjects for comparison, stronger analyses and allow more confidence in the conclusions drawn.

Since depression is a complex disorder, these studies will allow for the examination of a sub-population of individuals with depression, namely those with schizophrenia and comorbid depression. Ultimately, the proposed studies will allow for the identification of immune genes that may contribute to comorbid depressive states. Furthermore, the findings would provide a core basis that could be used as a starting point for examining immune genes in individuals with full-blown major depressive disorder.

Automatic Implantable Cardiac Defibrillators (AICDs) are life saving devices implanted in cardiac patients with increasing frequency. These devices come with psychiatric complications, including depression and anxiety, potentially requiring psycho- and pharmaco-therapeutic treatment to improve quality of life and possibly decrease frequency of deleterious cardiac outcomes. However, there are potential challenges in this population that require special attention in order to develop treatment plans that are practical, effective, and (eventually) empirically-validated. At present, there is no gold standard intervention for treating AICD-related depression and anxiety. This study represents the first step in the process of developing effective therapeutic interventions for AICD-related depression and anxiety.

The overall goal of the study, designed as a two-pronged qualitative study, is to gather comprehensive information about the experience of AICD-related depression and anxiety symptoms and the possible treatment needs of these patients. This information will be used to guide treatment recommendations, modify current interventions for the treatment of depression and/or anxiety for use in a cardiac population with AICDs, or to develop standardized interventions for the treatment of AICD-related depression and anxiety.

The primary objective of Dr. Drag’s study is to use fMRI and cognitive testing to examine the white matter disruptions in frontostriatal circuits that underlie psychomotor and cognitive dysfunction among older adults with late-onset depression. Because psychomotor dysfunction is a common and often disabling symptom of late-onset depression, a better understanding of the pathophysiology underlying these psychomotor changes is an important step towards identifying appropriate treatment strategies. Identifying a link amongst frontostriatal circuits, cognitive functioning, and psychomotor functioning can also have important implications for other populations with similar white matter changes, such as older adults with Bipolar Disorder or individuals with vascular dementia.

David Tai Hsu, Ph.D.The Role of Endogenous Opioids in Regulating the Response to Social Rejection and Acceptance in Major Depressive Disorder (2009)

The overall goal of Dr. Hsu’s research is to identify the link between social distress (e.g., marital discord, school bullying, social isolation) and major depressive disorder (MDD). Dr. Hsu’s 2009 award project has successfully led to a larger project examining the opioid response to positive and negative social feedback in both healthy participants and those with MDD. The endogenous opioid system is of high interest because it plays a role in regulating the effects of social and emotional stress. Preliminary results show pronounced differences between healthy and MDD participants in their opioid responses to social rejection and acceptance.

These findings will help to biologically define the contributions of an individual’s social environment to mental health, and further the U-M Depression Center's mission to reduce prevalence of these often debilitating disorders through effective early preventative intervention and/or innovative treatment strategies. To continue and extend this project, additional external funding has been provided from a MICHR High-Tech/Seed Grant, and an NIH Mentored Research Scientist Development Award (K01). An application to the National Alliance for Research on Schizophrenia and Depression is also under review.

Michelle Kees, Ph.D.Risk, Resilience, and Mental Health in Solders and Spouses before Military Deployment (2009)

Dr. Kees’ project seeks to build knowledge about the mental health and adjustment of National Guard soldiers and their spouses prior to an impending military deployment. The study seeks to characterize current mental health status and risk and resilience factors in the population, and to help fill a gap in available data about pre-deployment data, particularly with spouses. Ultimately, the project hopes to highlight areas to target for intervention prior to and during deployment and establish the first step in prospectively evaluating long-term adjustment and the impact of deployment experiences on mental health in soldiers and their spouses. Services are clearly needed for soldiers and families post-deployment; however, there is a window of opportunity before deployment that is largely ignored. Identifying and addressing the needs of military families sooner may better prepare them for deployment and provide critically timed prevention strategies to minimize adverse outcomes during and following deployment. This research has also received support from the Berman Research Fund.

Minden Sexton, Ph.D.Development of a Web-Based Psychotherapeutic Intervention for Depression during Pregnancy (2009)

Dr. Sexton’s project involves the development of a web-based intervention for women experiencing prenatal distress. This research aims to adapt an empirically-supported therapy modality (Cognitive Behavioral Therapy) to meet the unique needs of women during pregnancy and translate the developed package to a web-based intervention. Given the prevalence of depression in this population and its negative effects on both the mother and the developing fetus, identifying effect intervention strategies is imperative. The use of an online intervention is anticipated to circumnavigate common obstacles likely resulting in greater uptake of treatment and improvement in psychological functioning during pregnancy.

The overall goal of Dr. Berman’s research has been to contribute to the process of early detection of depression during pregnancy and intervention. Impaired fetal growth has known profound implications for newborns and represents a critical public health problem. Recent advances have been made in identifying the significant role of maternal depression in low birth weight as well as other fetal outcomes. However, identification of the association between depression and altered fetal growth frequently occurs postpartum, too late for effective intervention. There is a pressing need to increase early detection of the relationship between depression, psychiatric conditions and fetal health, thus allowing for critically important, timely steps to ensure the health of mother and child.

In this preliminary project, Dr. Berman and her team seek to answer a number of key research questions. These questions include: Is there a relationship and predictable pattern between maternal depression, severity of depressive symptoms and abnormal fetal growth as determined by prenatal ultrasound? Additionally, does this relationship correlate with alterations in neuroendocrine markers obtained from cord blood at the time of birth and are these growth alterations confirmed by the presence of small for gestational age infants? As the team completes its analyses, they will focus on additional clinical questions about altered fetal growth patterns in depressed mothers.

Alan R. Prossin, M.D.Relationship between immunological and central neurotransmission in healthy controls and in matched subjects diagnosed with MDD (2008)

Dr. Prossin’s project aims to contribute to the development of a greater understanding of the impact of the inflammatory system on human emotion. Such results have great potential to guide development of novel tools for use in the risk stratification and treatment selection in mood disorders. Additionally, a broader knowledge of endogenous human inflammatory processes opens the door to exploring the efficacy of immune altering treatments as novel strategies for treatment resistant depression.

The acquisition of data for this project has been completed, and two manuscripts have been produced. The pilot data resulting from this project has been included in a successful NIMH R21 award in collaboration with researchers at the University of Iowa that will form the basis of a biological screening/risk assessment strategy for post-partum depression. This study’s data will be used in support of additional grant submissions to support the development and investigation of novel treatment strategies for treatment resistant depression.

Leslie Swanson, Ph.D.Development of a Psychotherapeutic Treatment for Insomnia and Postpartum Depression (2008)

Dr. Swanson’s project involves developing and testing the benefits of a non-pharmacological sleep intervention for women with postpartum depression. The majority of these women do not achieve remission under the current standard of care, conferring risk to themselves and their offspring. The long-term goal of this research is to identify and develop innovative sleep interventions to enhance and optimize treatment outcomes for childbearing women.

In a series of focus groups with women diagnosed with postpartum depression and insomnia, participants were asked to provide information on sources of sleep disruption and how sleep impacts their mood. The following themes emerged: women with postpartum depression believe that insomnia has a substantial negative impact on their mood; they describe a great need for treatments to help them sleep, but they strongly prefer nonpharmacological treatments for sleep over medications because they are concerned about sleep medications impairing their ability to attend to their infant at night, and they are concerned about transmitting the medication to their breastfeeding infants; they believe treatment for sleep problems should occur at the same time as treatment for their mood.

Dr. Swanson and her research team have used the focus group data to develop a modified version of cognitive-behavioral therapy for insomnia (CBTI) for use by postpartum women, and are piloting the treatment in a sample of women with postpartum depression and insomnia to evaluate feasibility and preliminary effectiveness. Preliminary data show improvements in mood and sleep for women who completed the treatment. The data from the focus groups and treatment pilot were used to support an application for external funding, which is currently under review at NIH.

Cortney Turner, Ph.D.Involvement of the Fibroblast Growth Factor (FGF) System in Major Depressive Disorder (2008)

The goal of Dr. Turner’s clinical research study was to determine whether genetic variants in fibroblast growth factor 2 (FGF2), a chemical important in brain development, relate to an underlying endophenotype in major depressive disorder. Another aim of the project was to find out whether single nucleotide polymorphisms in FGF2 might be correlated with the response to an environmental or neuroendocrine challenge. Dr. Turner’s project has resulted in collecting 60 genomic DNA samples, with an equal number of cases and controls, and she is planning the first stage of genotyping.

Prior to this award, Dr. Turner identified the FGF system as playing a role in depression and anxiety using animal models. Specifically, FGF2 acted as both an antidepressant and anxiolytic (a factor in reducing anxiety). This work has the potential to significantly impact the field, since genetic variants in FGF2 may represent biomarkers for a specific endophenotype or stress reactivity in depression. Dr. Turner is planning the first stage of genotyping, an analysis which should yield sufficient preliminary data for a K01 award application.

Haiming Chen, M.D.A Pilot Program to Study the Pharmacogenomics of Lithium (2007)

Identifying biomarkers for predicting outcomes of lithium treatment in individuals with bipolar disorder is a long-term objective of Dr. Chen’s project. Lithium is one of the most effective treatments for bipolar disorder, but not all patients respond, with reported rates of non-response ranging from 20% to 50%. Evidence of lithium response is based on clinical observation, which requires a medication trial lasting often longer than four weeks, and there are no reliable biological predictors of response. The strength of lithium is in the longer term maintenance therapy of BPD, with the aim of preventing recurrence of episodes. Therefore, the discovery of biomarkers that would assist in early prediction of treatment outcome would be highly desired.

Dr. Chen and his team are focusing on identifying a set of genes based on results from this pilot study to develop blood-based laboratory tests to distinguish lithium responders from non-responders. This could result in more effective treatment of bipolar disorder, as well as advances in individualized medicine in this field. This will contribute to the Depression Center's mission to facilitate translation of cutting-edge clinical science to reduce prevalence of this often debilitating disorder through effective, early preventative intervention, and to treat the illness more effectively through early diagnosis of treatment responsiveness.

Thane Erickson, Ph.D.Pilot Studies of the Relation of Ego/Ecosystem Goals to Negative Affective States and Cortisol Response (2007)
This research entails two complementary pilot studies exploring the relations between goal orientations, social support, and the outcome variables of negative affectivity (i.e., depression and anxiety) and cortisol response. The purpose of the first study is to link goal orientation to depressive and anxiety symptoms in an experience-sampling study with a clinical sample, whereas the second study will experimentally manipulate goal cognition to observe impact on negative affect and cortisol responses.

Although currently available treatments for depression are effective for many individuals, about one-third of patients do not achieve remission even after several sequential treatment trials. These individuals are said to have “treatment-refractory depression” (TRD), and they experience the greatest functional impairment, disability, morbidity, mortality, and economic costs. To help these individuals and others who live with depression, more effective and individually tailored treatments are urgently needed. A major barrier to development of better treatments has been our limited understanding of the diverse pathophysiological mechanisms of depression. Characterization of key risk genes and plasma biomarkers in TRD patients is expected to help overcome this barrier by clarifying mechanisms of TRD. This greater understanding is, in turn, likely to inform diagnosis and individualized treatment of mood disorders.

This project will study biomarkers in treatment refractory depression (TRD), an important component of Dr. Mickey’s research on severe and refractory depression. The study aims to establish a cohort of patients with TRD, monitor their longitudinal outcomes, and test for association with genetic variants and plasma biomarkers putatively involved in the pathophysiology of depression. The goal of this project is to create pilot data that can be used to apply for external funds and to create a longitudinal cohort of patients that could be studied with brain imaging.

Maria Muzik, M.D., M.S.Maternal Anxiety during the Childbearing Years (2007)

This longitudinal study examines maternal trauma history and posttraumatic stress across the early postpartum period: 0 to 18 months postpartum. Specifically, MACY aims to better understand the interactions between infant genetics and maternal parenting behavior within the context of maternal posttraumatic stress, as it may create risk or resiliency for subsequent childhood psychiatric illness. The MACY study currently includes 224 mother-child infants and will continue recruiting until the sample reaches 300 participants.

The results of preliminary analyses conducted across varying dimensions of parenting, social support, demographics, and child outcomes in the early postpartum period indicate that maternal psychopathology (posttraumatic stress and depressive symptoms) is meaningfully associated a wide spectrum of adverse child outcomes: more infant sleep problems, difficult infant temperament, elevated infant stress hormone (cortisol) following interactive challenge, and finally higher levels of toddler behavior problems at 18 months postpartum. In addition, the study confirms a gene-by-environment influence on child development, as infants with 2 copies of the risk alleles in the Serotonin Transporter Gene who were also exposed to parenting risk showed worse developmental outcomes.

The knowledge that gained from the MACY study will greatly impact what is known of maternal psychiatric illness and its influence on child outcomes. The present study is consistent with the overarching research goal of gaining a more comprehensive understanding of how a mother’s trauma experience and psychopathology influences her caregiving capabilities and her child’s outcomes, and perhaps most importantly, how early intervention in these trajectories can be implemented in order to ameliorate risky outcomes for both mother and child across development.

Kara Zivin, Ph.D.Effectiveness of the M-DOCC model for improving depression and work productivity outcomes (2007)

This project, which evaluated the effectiveness of the M-DOCC (Michigan Depression Outreach and Collaborative Care) model for improving depression and work productivity outcomes, is complete. From this project, Dr. Zivin and her team also implemented the World Health Organization Health and Work Performance Questionnaire (HPQ) into the MSTRIDES system.

The long term objective of this work is to increase access to and quality of care for depression, to prevent productivity and job loss, as well as to provide support for return-to-work interventions for those missing or reducing work due to depression. This work will further the Depression Center's objective of reducing the negative health and social effects of depression in society. This pilot funding was useful in advancing Dr. Zivin’s research portfolio in the areas of depression care management and the relationship between depression and employment, and she plans to submit a proposal for external funding on the impact of mental disorders on employment.

The aims of the Physical Activity and Sleep Study (PASS)included the delineation of components for an exercise intervention in adolescents with depression. Dr. Dopp and his team have developed an intervention protocol that assists adolescents with depression to make significant increases in their physical activity levels. In addition, the research team has completed a pilot, feasibility study in which 100% of the participants completed 12 weeks of an exercise intervention. All participants showed a significant reduction in their depressive symptoms.
The pilot funding from the Rachel Upjohn Clinical Scholars Award positioned the research to compete for additional funding including 1) the Klingenstein Third Generation Foundation Fellowship in Childhood and Adolescent Depression, 2) the Gilmore Fund for Sleep Research and Education, and 3) a MICHR pilot seed grant award to measure serum biomarkers before and after 12 weeks of exercise intervention.

In addition to the evidence base for psychotherapies and medications, this project is one of the few studies examining exercise as treatment for adolescents with depression and has shown that future research in this area is feasible. In the future, Dr. Dopp hopes to establish the efficacy and cost-effectiveness of exercise interventions in both clinical and community settings.

Keith Sudheimer, Ph.D.The Role of Cortisol in Depression and Emotion(2006, 2004)

This study involved the use of fMRI to measure hemodynamic changes associated with cortisol. By comparing two groups of individuals, one of whom received small doses of hydrocortisone, the research examined brain circuits involved in the regulation of emotional responses. The role of cortisol and the HPA axis in emotional disorders, such as depression, has been studied for years, but there had been virtually no neuroimaging work linking this peripheral hormone with central nervous system activity.

The primary findings from the study were that cortisol administration in the form of hydrocortisone decreases sadness related brain activity in the subgenual cingulate cortex. This is a major finding, since it is known that endogenous cortisol is dysregulated in depression, and that subgenual cingulate cortex is also overactive in depression. This project is the first to demonstrate a plausible physiological link between these two symptoms, such that cortisol insensitivity (tolerance) in depression may be actually causing the brain activity changes observed in these patients. This project represents an important step in the understanding of how the dysregulation of cortisol is linked to abnormalities in brain activity and emotional processing. Although this project studied healthy subjects only, it demonstrated the physiological effect believed to underlie the brain changes in depression. Sudheimer continues to study cortisol's effect on emotion processes in depressed patients at Stanford University as a postdoctoral fellow, while his U-M mentors and colleagues continue to study the effects of exogenous cortisol on cognitive/emotional interactions.

Dr. Villafuerte’s project is studying a large number of genetic variations from 114 genes and personality traits as risk factors for mental illness. Genes were selected from the following biological pathways: serotonin, dopamine, adrenergic, GABA, circadian, HPA axis, neuroplasticity, immune, galanin, substance P, and Neuropeptide Y. The initial focus of the project was on Circadian genes. In a large collaboration study, Dr. Villafuerte and her team have replicated an association with a SNP (single nucleotide polymorphism) in the 3’ region of the CLOCK gene and the personality trait Agreeableness. Furthermore, a SNP in the CLOCK gene previously associated with an array of phenotypes was also associated with three personality traits, Agreeableness, Conscientiousness and Activity (an Extraversion facet). In addition, several SNPs in NPAS2 are associated with the personality traits Openness and Extraversion.

Based on the results of this pilot study, Dr. Villafuerte and her team is currently examining the effect of the CLOCK SNP on circadian properties (length, expression level and amplitude) in lymphocyte cell lines derived from bipolar patients with and without rapid cycling and control subjects. The goal is to investigate the effect of genetic variation on circadian properties of genes from this system. Genes from the serotonin system are also under investigation. Several SNPs from TPH1 and HTR2A were associated with Extraversion and Conscientiousness, respectively. When analyzing all associated SNPs in haplotypes, the association is stronger, confirming that these genes are associated with personality traits. Once all genes are analyzed, Dr. Villafuerte and her team plan to apply complex models to determine how these genes may interact with each other.

The primary objective of this pilot project was to better understand the interaction of depression and age in predicting cognitive function. Secondarily, this project sought to identify whether alterations to HPA-axis (hypothalamic-pituitary-adrenal) functioning might mediate this interaction. Preliminary findings support the double burden hypothesis of depression and age, particularly for executive functioning performance. Findings regarding HPA-axis functioning are more complex, suggesting non-linear relationships of HPA-axis functioning and cognition among older patients with depression.

This research will be of value in informing the chemoarchitecture of treatments to protect and enhance underlying neural circuits and in improving prediction of the course of depression among older adults.
The findings have been included in a VA Career Development Award application that proposes an investigation of cognitive, clinical, and neural markers of late life depression, and the extent to which baseline measures in these domains can predict function over time. Data gathered through this award were included in the application that led to Dr. Wright’s five-year VA Rehabilitation Research and Development Level-2 Career Development Award.

This project’s goal was to further understand the genetics of psychiatric disorders, especially mood disorders, and to identify variants that affect the risk of developing a mood disorder. The research involved analyzing data from genetic studies and developing statistical methods for analyzing both linkage and association data. It also aimed to develop a novel and innovative approach to address the problem of genetic heterogeneity in bipolar disorder, by studying sub-phenotypes, such as psychosis, to identify clinical subtypes that correspond to specific genetic variants by scanning the entire data set for patterns of multiple sub-phenotypes that co-occur among affected family members.

The primary aims of Dr. Arnedt’s study were to determine the preliminary efficacy of an eight-week nonpharmacological sleep treatment specific to patients with Major Depressive Disorder (MDD) for improving sleep, mood, and clinician-rated improvement, and to determine which sleep and mood measures predict clinical response to nonpharmacological sleep treatment.

Cognitive-behavioral therapy for insomnia (CBT-I) reduced the number of minutes spent awake during the night and improved sleep efficiency. Improvements were also found on the Insomnia Severity Index and the Pittsburgh Sleep Quality Index. Based on the findings from this pilot study, the study team concluded that improvements in sleep quality and self- and clinician-rated mood measures were evident following CBT-I and that baseline sleep variables were related to mood changes. These findings were used as preliminary data for an ongoing NIMH-funded R01 application, which aims to evaluate the efficacy and safety of adjunctive early and late partial sleep deprivation (one of the behavioral techniques used in CBT-I) compared to no sleep deprivation for augmenting the effects of eight weeks of fluoxetine 20-40 mg treatment in individuals with MDD. The project will also examine the underlying sleep mechanisms of treatment response.

The long-term objective of this research line is to improve the effectiveness of currently available depression treatments through adjunctive sleep-focused interventions and to identify the sleep-related mechanisms involved in the development and maintenance of mood disorders. Ultimately, the goal is to modify sleep markers of disease to reduce the prevalence and burden of these debilitating disorders.

The goal of this study was to identify subtypes of bipolar disorder that are important for genetics research. This project was the launching point for a larger, longitudinal study of bipolar disorder funded by the Heinz C. Prechter Bipolar Research Fund that will enable for much larger investigations into the genetics of bipolar disorder. The Genes and Subtypes of Bipolar Disorder project led to several publications, including an analysis of familiarity of subtypes of bipolar disorder, a linkage study of bipolar disorder in families with alcohol dependence and abuse, and a phenotypic study of anxiety in bipolar disorder. The study also led to the development of the idea of working with phenotypes, which the study group has refined to pursue several lines of research, including investigations into the relationship between personality and bipolar disorder and sleep disturbance in bipolar subjects. By finding clinical types of bipolar disorder that can be pursued for biological and genetic studies, both etiological and interventional research can be targeted in a careful and clinically relevant way.

Dr. Heitzeg’s project was designed to examine the function of neuroanatomical networks involved in the regulation of emotional function in teenagers at risk for the development of a major depressive episode and other psychopathology in adulthood, based on their prior exposure to stressful life events. The aims were to use functional MRI to characterize the effect of early life stressors on the functional responses of brain regions implicated in the regulation of emotional states, and determine whether this effect is different in males and females. Functional MRI (fMRI) was conducted on 60 participants (30 males and 30 females) during a lexical affect task, as proposed.

The long-term objective of this project is to provide a neurobiological framework for the understanding of risk factors conferring predisposition to the development of psychopathology. Ultimately, this data could be integrated into the development of more aptly targeted, individualized strategies for the prevention of psychopathology. This project allowed the collection of initial data that eventually led to a K01 award from NIDA (2005-2010) and then an R01 from NIDA (2009-2014) to study risk trajectories for psychopathology.

Dr. Langenecker’s project was based upon the premise that for a subset of individuals suffering from depression, abnormalities in emotion perception might be relevant to understanding the underlying neurobiology of depression and how these abnormalities might relate to treatment response. This series of studies found that emotion-processing weaknesses are indeed present in major depressive disorder (MDD) and are prevalent in younger females and older males and females, but not in younger males with depression.

The Rachel Upjohn Clinical Scholars award proved to be an instrumental, necessary, and critical award in starting the line of research on emotion-processing abnormalities in MDD and related disorders. In the end, it will have nearly fully funded two studies and provided seed data for grants and additional papers. The line of work begun with this award provides a critical, translational link of cognitive and affective neuroscience with instruments that could be used in clinical settings. The team now has two replicated behavioral metrics with the task, anger bias in responding to sad and fearful faces, plus overall accuracy in emotional classification of faces, that can be administered by technicians in clinical settings and can be repeated over time. In addition, these behavioral deficits could be the target of social skills treatments and cognitive behavioral interventions.

Dr. Hirshbein’s initial awarded project has evolved into a larger project on the history of depression. Its original aims were to look at the ways in which depression appeared in popular culture over the Twentieth Century to better understand sources of information utilized by patients, as well as to explore how popular ideas about gender affected discussions about depression. Findings from this project were published in a major monograph (Hirshbein, Laura D. American Melancholy: Constructions of Depression in the Twentieth Century. New Brunswick, NJ: Rutgers University Press, 2009) and were also presented in a variety of other venues.

The Rachel Upjohn Clinical Scholar award allowed Dr. Hirshbein to begin the initial work that helped her to build bridges between clinical psychiatry and the history of medicine. The award has served as a solid foundation for Dr. Hirshbein to continue researching the history of psychiatry, as well as to develop collegial relationships with other clinician-historians. The funding from this award also enhanced Dr. Hirshbein’s ability to receive additional funding for her work from the National Library of Medicine.

Dr. Phan’s project aims were to examine the circuitry underlying brain responses to emotionally salient visual stimuli and help describe the brain regions involved in different aspects of emotion using functional magnetic resonance imaging (fMRI). The brain-based model on emotion and individual differences became the foundation to which the laboratory has developed the research team’s understanding of the neural mechanisms that underlie anxiety disorders such as posttraumatic stress disorder and social anxiety disorder. Pilot funding from this work subsequently lead to Dr. Phan’s K23 Award from the NIH.

This study discovered that people can use personal information (an individual's own experience) to better understand how their own brain works. By understanding individual differences in how the brain processes salient information, one is better informed about perception, understanding, response, motives and actions at a very personal level. That is, although patients may share a common illness (anxiety, depression, schizophrenia, bipolar disorder, addiction), each person processes the environment in different ways, taking into account important contextual factors, including one’s own personality, past experiences, and future goals. This helps tailor the most personalized treatment approach for each of our patients.